Safety and efficacy of a novel injectable anti-TNF-α/anti-VEGF drug delivery system for corneal and retinal protection after injury.

Abstract

Purpose : To develop a novel therapy to suppress acute and long-term ocular complications after injury by using an injectable thermosensitive drug delivery system (DDS) for sustained subconjunctival delivery of anti-TNF-α and anti-VEGF reagents.

Methods : A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock) loaded with 2mg of infliximab and aflibercept (1:2; Infli/Afli) was injected subconjunctivally in 3 Dutch-belted rabbits after corneal alkali injury. Control rabbits received human IgG loaded DDS (n=4) or only aflibercept DDS (n=3). Animals were followed for 3 months and assessed in vivo for tolerability, corneal neovascularization (CoNV), re-epithelialization, and ex vivo for retinal ganglion cell (RGC) loss, optic nerve axon loss, and expression of inflammatory markers. Drug release kinetics was assessed in-vitro by using fluorescein-dextran as a model drug, and in-vivo by aqueous humor analysis.

Results : Infli/Afli DDS treatment led to complete suppression of CoNV for over 3 months without adverse effects or reactions by the eye, while aflibercept DDS showed mild CoNV (~10% of cornea) and IgG DDS significantly more CoNV (~ 30% of cornea). Eyes treated with Infli/Afli DDS showed minimal corneal epithelial defect (0-2% of cornea) over 3 months, while IgG DDS treated eyes exhibited epithelial defect up to 11% of the cornea area albeit wound closure at 3 months. Aflibercept DDS group exhibited persistent corneal epithelial defects (~7% at 3 months). Histologically, Infli/Afli DDS reduced CD45⁺ immune cell accumulation (92%, P<0.05) and ameliorated TNF-α expression (70%, P<0.05) in the cornea, as compared to IgG DDS. Subconjunctival administration of infli/afli DDS achieved sustained retinal drug diffusion, and prevented RGC loss as compared to the other two groups at 3 months which exhibited 33-63% RGC loss. Quantification of IgG content in the aqueous humor using ELISA assay demonstrated that the DDS provided sustained, first-order drug release for over 3 months.

Conclusions : Sustained subconjunctival administration of infliximab and aflibercept using a thermosensitive biodegradable DDS that targets TNF-α and VEGF signaling pathways is an extremely effective therapy for preventing post-injury corneal inflammation and neovascularization, while providing the much needed retinal protection against RGC loss. Further studies are warranted.

This is a 2021 ARVO Annual Meeting abstract.